Proteolytic activation transforms heparin cofactor II into a host defense molecule.

Area of Science:

• Biochemistry
• Immunology
• Molecular Biology

Background:

• Heparin cofactor II (HCII) is a serine proteinase inhibitor with a proposed role in inhibiting extravascular thrombin.
• The precise physiological function of HCII in the body has remained unclear.

Purpose of the Study:

• To investigate a previously unrecognized function of HCII in host defense mechanisms.
• To elucidate the molecular basis for HCII's potential role in immunity.

Main Methods:

• Inducing conformational changes in HCII through proteolytic cleavage.
• Mapping functional epitopes using peptide analysis.
• Assessing host defense in HCII-deficient mice challenged with Pseudomonas aeruginosa.
• Quantifying HCII levels in wild-type mice after bacterial or endotoxin challenge.
• Detecting cleaved HCII forms in human wound and bacterial samples.

Main Results:

• Proteolytic cleavage of HCII induced conformational changes, conferring endotoxin-binding and antimicrobial properties.
• HCII-deficient mice exhibited increased susceptibility to Pseudomonas aeruginosa infection and heightened cytokine responses.
• Wild-type animals showed reduced HCII levels following bacterial or endotoxin exposure.
• Proteolytically cleaved HCII was identified in human wound sites and associated with bacteria.

Conclusions:

• Protease-induced conformational changes in HCII uncover cryptic epitopes, transforming it into a host defense factor.
• This mechanism represents a novel regulatory pathway in HCII biology and innate immunity.
• HCII plays a significant role in combating invasive bacterial infections and modulating immune responses.